Antihypertensive sulfur-containing compounds

ABSTRACT

Novel S-substituted mercapto-lower alkanoyl-4-thiazolidinecarboxylic acids, -2-pyrrolidinecarboxylic acids and their esters represented by the general formula ##STR1## wherein Q is methylene or sulfur; 
     Z is straight or branched alkylene with 1 to 3 carbon atoms, their process for manufacturing, the antihypertensive composition comprising these compounds and the method for reducing blood pressure.

This is a division of application Ser. No. 86,996 filed Oct. 22, 1979.

DETAILED EXPLANATION OF THE INVENTION

This invention relates to sulfur-containing compounds which are useful as antihypertensive agents. These compounds are represented by the following formula [I] and salts thereof. ##STR2## wherein

Q is methylene or sulfur;

R^(a) is R¹ or R⁹ ;

R^(b) is R², R⁴, R⁶, R⁸ or R¹⁰ ;

R^(c) is R³, R⁵ or R⁷ ;

but when Q is methylene, R^(b) is R², R⁴ or R¹⁰, and R^(c) is R³ or R⁵ ;

when Q is sulfur, R^(b) is R⁶, R⁸ or R¹⁰, and R^(c) is R⁵ or R⁷ ;

and when R^(b) is R², R^(c) is R³ ;

when R^(b) is R⁴ or R⁸, R^(c) is R⁵ ;

when R^(b) is R⁶, R^(c) is R⁷ ;

when R^(b) is R¹⁰, R^(c) is R⁵, and R^(a) is R⁹ ;

R¹ is hydrogen;

R² is lower alkyl, aralkyl, lower alkanoyl, cycloalkanecarbonyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, halogen or lower alkoxy;

R³ is higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;

R⁴ is higher alkanoyl, naphtoyl, ##STR3## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is hydroxy, phenyl-lower alkoxy, acyloxy, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy;

R⁵ is hydrogen, lower alkyl, higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted lower alkyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;

R⁶ is acetyl;

R⁷ is higher alkyl, cycloalkyl, aralkyl, furyl, thienyl, pyridyl, naphthyl or substituted phenyl wherein the substituent(s) is acyloxy, mercapto, acylmercapto, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy;

R⁸ is lower alkyl, lower alkanoyl except acetyl, higher alkanoyl, cycloalkanecarbonyl, aralkyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphtoyl, ##STR4## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, arylamino, acylamino or carboxy;

R⁹ is phenyl, alkoxy-lower alkyl, acyloxy-lower alkyl, imido-lower alkyl or substituted phenyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, acyl, acyloxy, halogen, nitro, amino, lower alkylamino, acylamino or carboxy;

R¹⁰ is lower alkyl, lower alkanoyl, higher alkanoyl, cycloalkanecarbonyl, aralkyl, benzoyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, naphtoyl, ##STR5## substituted lower alkyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, acyloxy, halogen, mercapto, acylmercapto, nitro, amino, lower alkylamino, acylamino or carboxy;

Z is straight or branched alkylene with 1 to 3 carbon atoms (e.g., --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ --, --CH(CH₃)CH₂ --);

in the formula,

lower alkyl or lower alkylene is straight or branched chain with 1 to 6 carbon atoms;

higher alkyl is saturated or unsaturated, straight or branched chain with 7 to 20 carbon atoms;

aralkyl is benzyl, etc.;

acyl is acetyl, propionyl, pivaloyl, etc.;

lower alkanoyl is acetyl, propionyl, pivaloyl, etc.;

higher alkanoyl is octanoyl, linoloyl, etc.;

lower alkoxy is methoxy, ethoxy, etc.;

aryl is 3-trifluoromethylphenyl, etc.;

imido is succinimido, phthalimido, etc.

The same shall be applied hereinafter.

The compounds [I] of this invention are ester derivatives and/or S-acyl or S-alkyl derivatives of mercaptoacylamino acids, the known effective angiotensin I-converting enzyme inhibitors, and they release mercaptoacylamino acids which are proved efficacious at the part to be shown the activity by enzymatic and/or chemical hydrolysis when administered to men or animals. Mercaptoacylamino acid is easy to be subjected to the reactions such as oxidation, etc. during the manufacture thereof or with time lapse in the living body because it contains sulfhydryl group in its molecule, and therefore possesses the problems, that is, the decrease in activity and shorter effective hours. On the other hand, the protection of sulfhydryl group by acyl particularly benzoyl can make the activity long lasting and simultaneously the lipophilic property increase, and therefore the absorption potency can be improved. But, in the known S-benzoyl derivatives, the effective time cannot be prolonged to a desirable extent because they are immediately deacylated by hydrolysis or metabolism in the living body after absorbed. So, in this invention, to achieve the aim at lasting the effect as long as possible, various substituents are introduced to benzoyl group as acyl group protecting the sulfhydryl group in mercaptoacylamino acid. As the result, it has been proved that the compounds of this invention can make the effective time longer than S-benzoyl derivatives. Furthermore, esterification of carboxylic acid can also increase the lipophilic property of mercaptoacylamino acid, and therefore the absorption potency can be further improved and the activity can be further prolonged. In addition, thioester of mercaptoacylamino acid and various diuretic such as ethacrynic acid and furosemide, etc. is also efficacious. Besides, as the unstable sulfhydryl group is protected by acyl or alkyl group, the compounds of this invention have the property that the activity is hard to decrease particularly by oxidation, etc., and the medicinal preparation is more stable than the antihypertensive compositions containing the known mercaptoacylamino acids as main ingredient so that it may not show the lowering of activity, or the generation of offensive odor, etc. through decomposition during the manufacture thereof or with time lapse.

The compounds [I] of this invention are synthesized by such methods as the following A, B and C.

(A) The compounds represented by the formula

    R.sup.b --S--Z--CO--X                                      [II]

wherein X is hydroxy or halogen; the same shall be applied hereinafter

are reacted with the compounds represented by the formula ##STR6## by a known method such as Schotten-Baumann reaction and mixed anhydride method to give the compounds of this invention represented by the formula [I].

(B) The compounds represented by the formula

    R.sup.b --X                                                [IV]

are reacted with the compounds represented by the formula ##STR7## by a known method such as Schotten-Baumann reaction and mixed anhydride method to give the compounds of this invention represented by the formula [I].

(C) The compounds of this invention represented by the formula [VI] are synthesized by the following method. ##STR8##

The compounds represented by the formula

    R.sup.9 --Y                                                [VII]

wherein Y is halogen;

are reacted with the compounds represented by the formula ##STR9## by a known method to give the compounds of this invention represented by the formula [VI].

The compounds of the formula [I] synthesized by the above methods can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, diethylamine salt, triethanolamine salt, etc.

The compounds of the formula [I] have the stereoisomers which are within the limit of this invention, because they have one or more asymmetric carbon atoms.

Examples are shown below, although this invention is not limited to these examples.

EXAMPLE 1 (4R)-3-[(2S)-S-(4-Methylbenzoyl)-2-mercaptopropanoyl]-4-thiazolidinecarboxylic acid (Compound 19)

2.2 g of (4R)-3-[(2S)-2-mercaptopropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.6 g of p-toluoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 3.3 g (97%), mp. 166°-166.5° C. (ethyl acetate), [α]_(D) ²⁵ -148.6° (c=1.1, methanol).

IR (nujol, cm⁻¹) 1766, 1650, 1620, 1605, 1428, 1215, 1208, 1174, 913.

NMR (CDCl₃, δ) 1.60 (3H, d, J=7 Hz), 2.40 (3H, s), 3.30 (2H, d, J=5 Hz), 4.63 (1H, q, J=7 Hz), 4.64, 4.93 (2H, ABq, J=7.5 Hz), 5.10 (1H, t, J=5 Hz), 7.22, 7.82 (4H, A₂ B₂, each d, J=8 Hz), 10.46 (1H, s).

Analysis (C₁₅ H₁₇ NO₄ S₂): Calcd: C, 53.08; H, 5.05; N, 4.13; Found: C, 52.98; H, 5.00; N, 4.10.

EXAMPLE 2 (4R)-3-[(2S)-S-Cyclohexanecarbonyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (Compound 9)

2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.8 g of cyclohexanecarbonyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.5 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.8 g (81%), mp. 79.5°-80° C. (benzene-n-hexane), [α]_(D) ²³ -176.2° (c=1.0, methanol).

IR (nujol, cm⁻¹) 1737, 1694, 1602, 1439, 1198, 972.

NMR (CDCl₃, δ) 1.25 (3H, d, J=6 Hz), 1.30-2.20 (10H, m), 2.50 (1H, m), 2.70-3.10 (3H, m), 3.32 (2H, d, J=5 Hz), 4.50, 4.77 (2H, ABq, J=8 Hz), 5.10 (1H, t, J=5 Hz), 10.20 (1H, s).

Analysis (C₁₅ H₂₃ NO₄ S₂): Calcd: C, 52.15; H, 6.71; N, 4.05; Found: C, 52.16; H, 6.66; N, 3.81.

EXAMPLE 3 (4R)-2-(2-Acetoxyphenyl)-3-(S-acetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid (Compound 32)

2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 1.8 g of S-acetyl-3-mercaptopropanoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 2.8 g (70%), mp. 144°-145° C. (ethyl acetate-benzene), [α]_(D) ²⁷ +109.0° (c=1.0, methanol).

IR (nujol, cm⁻¹) 1770, 1738, 1691, 1605, 1169, 907.

NMR (CDCl₃, δ) 2.27 (3H, s), 2.37 (3H, s), 2.10-2.80 (2H, m), 3.08 (2H, d.d, J=5.5, 6 Hz), 3.30 (2H, d, J=7.3 Hz), 4.97 (1H, t, J=7.3 Hz), 6.20 (1H, s), 7.00-7.50 (3H, m), 7.98 (1H, m), 10.18 (1H, s).

Analysis (C₁₇ H₁₉ NO₆ S₂): Calcd: C, 51.37; H, 4.82; N, 3.52; Found: C, 51.58; H. 4.75; N, 3.50.

EXAMPLE 4 (4R)-2-(2-Acetoxyphenyl)-3-[S-(4-methylbenzoyl)-3-mercaptopropanoyl]-4-thiazolidinecarboxylic acid (Compound 47)

2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 2.6 g of S-(4-methylbenzoyl)-3-mercaptopropanoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.6 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.7 g (57%), mp. 93°-96° C. (benzene), [α]_(D) ²⁴ +80.4° (c=1.0, methanol).

IR (nujol, cm⁻¹) 3560, 1768, 1721, 1635, 1204, 1178, 918.

NMR (CDCl₃, δ) 2.30 (3H, s), 2.38 (3H, s), 2.63 (2H, m), 3.10-3.50 (4H, m), 4.97 (1H, t, J=7.5 Hz), 5.61 (2H, br. s), 6.19 (1H, s), 6.90-8.20 (8H, m).

Analysis (C₂₃ H₂₃ NO₆ S₂.1/2H₂ O): Calcd: C, 57.25; H, 5.01; N, 2.90; Found: C, 57.51; H, 5.07; N, 2.62.

EXAMPLE 5 (4R)-3-[(2S)-S-(4-Acetylaminobenzoyl)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (Compound 27)

1.8 g of 4-acetylaminobenzoic acid is dissolved in 20 ml of dry tetrahydrofuran. To this solution, 1.4 ml of triethylamine is added. To this mixture, 1.3 ml of isobutyl chloroformate is added dropwise with stirring at -5° C. After ten minutes, to this solution, 20 ml of aqueous solution of 2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 1.4 ml of triethylamine is added, and the mixture is stirred at room temperature for 30 min. To this reaction solution, 40 ml of water is added, and the obtained mixture is washed with ethyl acetate. The aqueous layer is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.1 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 3.6 g (90%), mp. 206°-207° C. (methanol), [α]_(D) ²⁷ -152.5° (c=1.0, methanol).

IR (nujol, cm⁻¹) 3286, 1735, 1645, 1622, 1585, 1524, 1455, 1318, 1210, 1170, 913.

NMR (DMSO-d₆, δ) 1.18 (3H, d, J=6 Hz), 2.10 (3H, s), 2.70-3.50 (5H, m), 4.57, 4.88 (2H, ABq, J=9 Hz), 4.94 (1H, d.d, J=6, 3 Hz), 7.73, 7.87 (4H, A₂ B₂, each d, J=9 Hz), 10.30 (1H, s).

Analysis (C₁₇ H₂₀ N₂ O₅ S₂): Calcd: C, 51.50; H, 5.08; N, 7.07; Found: C, 51.32; H, 5.06; N, 7.02.

EXAMPLE 6 (2,2-Dimethyl-1-oxopropoxy)methyl (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylate (Compound 64)

Under a nitrogen atmosphere, to the solution of 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazoldinecarboxylic acid in 11 ml of dry N,N-dimethylformamide, 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate are added, and stirred at 90° C. for 6 hours. The reaction mixture is poured into 100 ml of ice-water, and extracted with ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.8 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 4.1 g (91%), mp. 69°-69.5° C. (benzene-n-hexane), [α]_(D) ²⁵ -153.8° (c=1.0, methanol).

IR (nujol, cm⁻¹) 1770, 1751, 1655, 1643, 1457, 1417, 1204, 1102, 990, 912.

NMR (CDCl₃, δ) 1.18 (9H, s), 1.30 (3H, d, J=6 Hz), 2.93 (1H, m), 3.17 (4H, m), 4.50, 4.77 (2H, ABq, J=8 Hz), 5.13 (1H, d.d, J=5, 6 Hz), 5.70, 5.80 (2H, ABq, J=6 Hz), 7.20-8.07 (5H, m).

Analysis (C₂₁ H₂₇ NO₆ S₂): Calcd: C, 55.61; H, 6.00; N, 3.09; Found: C, 55.73; H, 5.98; N, 2.97.

Tables I to VIII show various compounds and physical constants including the compounds specified in the examples.

                                      TABLE I                                      __________________________________________________________________________      ##STR10##                                                                                         Method                                                                         of                                                                             prepn.                                                     Comp.               (Examp.                                                                             Yield    Recrystn.                                                                             [α].sub.D                                                                         IRg.                         No.  R     R.sup.2  No.) (%) mp. (°C.)                                                                    solvent                                                                               (c, solv., °C.)                                                                  (nujol,                      __________________________________________________________________________                                                       cm.sup.-1)                   1    H     COCMe.sub.3                                                                             3    91  195-196                                                                             EtOAcben-                                                                               --     3180, 1719, 1676,                                                              1616,                                                          zene            1596, 1448, 1247               2  Me (S config.)                                                                        ##STR11##                                                                              1    94  183-184                                                                             EtOAcben- zene                                                                        -10.9 (1.0, MeOH,                                                                       3330, 1714, 1663, 1621,                                                        602, 1462, 910                 3  H                                                                                     ##STR12##                                                                               2*  80  oil         +42.5 (0.5, MeOH,                                                                       1723, 1645, 1605, 1175,                                                        13, 826 (CHCl.sub.3,                                                           cm.sup.-1)                   __________________________________________________________________________      *Starting material, thiol: mp. 197-198° C. (dec.) (EtOAcchexane),       [α].sub.D.sup.25 +34.7° (c = 0.5 MeOH), IR (nujol, cm.sup.-1      3360, 1720, 1685, 1605, 1585, 1280, 1165, 760.                           

                                      TABLE II                                     __________________________________________________________________________      ##STR13##                                                                            Method of                                                               Compd. prepn. Yield    Recrystn.                                                                           [α].sub.D deg.                                                                    IR                                        No.  R.sup.4                                                                          (Examp. No.)                                                                          (%) mp. (°C.)                                                                    solvent                                                                             (c, solv., °C.)                                                                  (nujol, cm.sup.-1)                        __________________________________________________________________________     4    * 5      63  42-45     -107.3   1723, 1665, 1635, 1590,                                               (0.9, CHCl.sub.3, 25)                                                                   1290, 1075 (CHCl.sub.3, cm.sup.-1)        5    **                                                                               5      74  121-124   -120.2   3320, 3240, 1725, 1625,                                               (1.2, MeOH, 25)                                                                         1595, 1560, 1382, 1340,                                                        1176, 1160                                __________________________________________________________________________      ##STR14##                                                                      ##STR15##                                                                                                                                               

                                      TABLE III                                    __________________________________________________________________________      ##STR16##                                                                                             Method                                                                         of                                                                             prepn.                                                 Compd.                  (Examp.                                                                             Yield     Recrystn.                                                                               [α].sub.D                                                                       IRg.                    No.  R.sup.8     R.sup.5                                                                               No.) (%) mp. (°C.)                                                                     solvent  (c, solv.,                                                                            (nujol,                 __________________________________________________________________________                                                            cm.sup.-1)              6    Me          H      2    84  126-127                                                                              EtOAc    -156.0 1722, 1605,                                                             (1.1, MeOH,                                                                           1344, 1264,                                                             26)    1201                    7    CH.sub.2 Ph H      1    92    98.5-99.5                                                                          benzene         1762, 1610,                                                                    1346, 1209,                                                                    1175, 835, 807          8    COC.sub.17 H.sub.31 **                                                                     H      2    74  oil            -202.1 1745, 1690,                                                             (0.5, CHCl.sub.3,                                                                     1635, 1460,                                                             24)    1380, 1095                                                                     (neat, cm.sup.-1)         9                                                                                  ##STR17##  H      2    81   79.5-80                                                                             benzene- -176.2 (1.0, MeOH,                                                                    1737, 1694, 1602,                                                              1439, 1198, 972           10                                                                                 ##STR18##  H      1    87  189-190.5*                                                                           MeOH     -114.8* (1.0, MeOH,                                                                   1685, 1635, 1555,                                                              1380, 900, 780*           11 COCH.sub.2 Ph                                                                              H      1    71  131-131.5                                                                            MeOH     -162.2 1735, 1682,                                                             (1.3, MeOH,                                                                           1600, 1200,                                                             24)    1010, 710                 12a                                                                                ##STR19##  H      2    35  118-118.5                                                                            (i-Pr).sub.2 O                                                                          -70.9 (0.9, MeOH,                                                                     1740, 1680, 1620,                                                              1390, 1210, 920           12b                                                                                ##STR20##  H      2    38  oil            -107.5 (1.1, MeOH,                                                                    1750, 1680, 1620,                                                              1390, 1210, 950                                                                (neat, cm.sup.-1)         13 ***         H      5    58   43-46         -100.0 1725, 1660,                                                             (0.4, CHCl.sub.3,                                                                     1588, 1290, 1074                                                        25)    (CHCl.sub.3,                                                                   cm.sup.-1)              14   ****        H      5    63  122-125        -125.6 3320, 3240,                                                             (1.1, MeOH,                                                                           1725, 1623,                                                             25)    1594, 1555,                                                                    1377, 1305,                                                                    1182, 1156                15                                                                                 ##STR21##                                                                                  ##STR22##                                                                            2    80  oil            -114.5 (1.0, MeOH,                                                                    1728, 1680, 1640,                                                              1418,                                                                          973 (CHCl.sub.3,                                                               cm.sup.-1)                16 CO.sub.2 CH.sub.2 Ph                                                                        ##STR23##                                                                            2    91  oil            -87.3 (1.0, MeOH,                                                                     1737, 1705, 1642,                                                              1414, 1237, 1146                                                               (neat, cm.sup.-1)         17 CO.sub.2 CH.sub.2 Ph                                                                        ##STR24##                                                                            2    83  oil            +31.5 (1.0, MeOH,                                                                     1738, 1704, 1653,                                                              1415, 1237, 1142                                                               (neat, cm.sup.-1)         18 CH.sub.2 CO.sub.2 H                                                                         ##STR25##                                                                            1    59  132-134                                                                              MeOHEtOAc       1725,                   __________________________________________________________________________                                                            1630                     *Dicyclohexylamine salt.                                                       **COC.sub.17 H.sub.31 is linoloyl.                                             ##STR26##                                                                      ##STR27##                                                                                                                                               

                                      TABLE IV                                     __________________________________________________________________________      ##STR28##                                                                                                Method                                                                         of                                                                             prepn.                 [α].sub.D deg.         Compd.                     (Examp.                                                                             Yield     Recrystn.                                                                              (c, solv.,                                                                           IR                     No.  R.sup.5    R.sup.11 n No.) (%) mp. (°C.)                                                                     solvent °C.)                                                                          (nujol,                __________________________________________________________________________                                                             cm.sup.-1)             19   H          4-Me     0 1    97  166-166.5                                                                            EtOAc   -148.6                                                                               1766, 1650,                                                              (1.1, 1620, 1605,                                                              MeOH,                                                                                1428, 1215,                                                                    1208, 1174, 913        20   H          2-Me     1 1    79  101- 103                                                                             benzene-                                                                               -175.6                                                                               3080, 1761,                                                      n-hexane                                                                               (1.0, 1660, 1614,                                                              MeOH,                                                                                1215, 1200,                                                                    910, 770               21   H          3-Me     1 1    85  113-115                                                                              benzene-                                                                               -145.2                                                                               3080, 1750,                                                      n-hexane                                                                               (1.0, 1652, 1612,                                                              MeOH,                                                                                1150, 808              22   H          4-Me     1 1    91  142-142.5                                                                            benzene -171.9                                                                               1755, 1646,                                                              (1.0, 1607, 1460,                                                              MeOH,                                                                                1206, 1176,                                                                    916                    23   H          4-Pri    1 1    76  143-145                                                                              benzene -161.2                                                                               1738, 1653,                                                              (1.0, 1607, 1179,                                                              MeOH,                                                                                921                    24   H          3,4-Me.sub.2                                                                            1 1    90  138-138.5                                                                            benzene -165.6                                                                               1755, 1654                                                               (1.0, 1610, 1440,                                                              MeOH,                                                                                830                    25   H          3,5-Me.sub.2                                                                            1 1    96  140-142                                                                              benzene -172.9                                                                               1734, 1648,                                                              (1.0, 1610, 1289,                                                              MeOH,                                                                                1218, 1154             26   H          2-OAc    1 5    53  117-119                                                                              benzene -163.2                                                                               3140, 1771,                                                              (1.0, 1755, 1652,                                                              MeOH,                                                                                1625, 1185,                                                                    931, 907               27   H          4-NHAc   1 5    90  206-207                                                                              MeOH    -152.5                                                                               3286, 1735,                                                              (1.0, 1645, 1622,                                                              MeOH,                                                                                1585, 1524,                                                                    1455, 1318,                                                                    1210, 1170,                                                                    913                      28 H                                                                                          ##STR29##                                                                              1 2    80   62-64        -185.4 (1.2, MeOH,                                                                   3280, 1740, 1620,                                                              1600, 1575, 1190,                                                              162, 1120, 905                                             147.5-149*                                                                           acetone-                                                                       MeOHether                              29                                                                                 ##STR30## 3,4,5-(OMe).sub.3                                                                       1 2    60  oil           -78.0 (1.1, MeOH,                                                                    1741, 1652, 1586,                                                              1325, 1232, 1129,                                                              003 (neat,                                                                     cm.sup.-1)             __________________________________________________________________________      *Dicyclohexylamine salt.                                                 

                                      TABLE V                                      __________________________________________________________________________      ##STR31##                                                                                         Method                                                                         of                                                                             prepn.                                                     Compd.              (Examp.                                                                             Yield    Recrystn.   [α].sub.D                                                                       IRg.                      No.  R.sup.12                                                                               R.sup.13                                                                           R  No.) (%) mp. (°C.)                                                                    solvent     (c. solv.,                                                                            (nujol,                   __________________________________________________________________________                                                          cm.sup.-1)                30   Me      2-OH                                                                               H  4    45   74-76.5                                                                            AcOEtether  +135.9*                                                                               3160, 1740, 1610,                                                       (1.0,  1590, 1455, 1380*                                                       MeOH, 26)                        31   Me      2-OMe                                                                              H  4    74   75-76.5                                                                            benzene     +129.3 1760, 1600, 1380,                                                       (1.0,  1240, 1030, 775                                                         MeOH, 24)                        32   Ac      2-OAc                                                                              H  3    70  144-145                                                                             EtOAcbenzene                                                                               +109.0 1770, 1738, 1691,                                                       (1.0,  1605, 1169, 907                                                         MeOH, 27)                        33   COEt    2-OH                                                                               H  3    54   89-92                                                                              EtOAcbenzene                                                                               +156.4 3250, 2650, 1740,                                                       (1.0,  1645, 1610, 1234,                                                              925                                                                     MeOH, 26)                        34   CO(CH.sub.2).sub.6 Me                                                                  2-OH                                                                               H  2    39  oil              +137.4 3260, 1726, 1654,                                                       (1.0,  1411, 1284, 1220,                                                       MeOH, 23)                                                                             1044 (CHCl.sub.3,                                                              cm.sup.-1)                35   COCMe.sub.3                                                                            2-OH                                                                               H  1    89  155-156                                                                             EtOAcbenzene                                                                               +140.9 3240, 1740, 1684,                                      (dec.)           (1.0,  1621, 1388, 938                                                         MeOH, 27)                        36   COCMe.sub.3                                                                            4-OMe                                                                              Me 1    73  140-141                                                                             benzene     +73.9  1723, 1663, 1610,                                                              964                                                                     (1.0,                                                                          MeOH, 26)                        37   COCMe.sub.3                                                                            2-OH,                                                                              H  3    82  147-148                                                                             EtOAcbenzene                                                                               +142.8 3290, 1710, 1693,                      3-OMe                            (1.0,  1270, 1063, 932                                                         MeOH, 28)                        38   COCH.sub.2 Ph                                                                          2-OH                                                                               H  2    85   57-59           +120.9 1724, 1680, 1650,                                                       (1.0,  1602, 1403                                                              MeOH, 25)                                                                             (CHCl.sub.3,                                                                   cm.sup.-1)                39   COCH.sub.2 Ph                                                                          2-OAc                                                                              H  2    63  oil              +72.0  1763, 1727, 1653,                                                       (0.8,  1637, 1605, 1400,                                                       MeOH, 24)                                                                             1198 (neat,                                                                    cm.sup.-1)                  40                                                                                 ##STR32##                                                                             2-OH                                                                               H  1    62  201-202 (dec.)   +157.2 (1.0, MeOH,                                                                    3360, 1730, 1675,                                                              1635, 1600, 925             41                                                                                 ##STR33##                                                                             2-OH, 5-Cl                                                                         Me 1    54  205-206 (dec.)                                                                       MeOHEtOAcben- zene                                                                        +105.5 (0.5, MeOH,                                                                    3190, 1729, 1672,                                                              1623, 1278, 1229,                                                              916                         42 CO.sub.2 CH.sub.2 Ph                                                                   2-OH                                                                               H  2    96  oil              +121.5 3290, 1707, 1629,                                                       (1.0,  1142, (neat,                                                                   cm.sup.-1)                                                              MeOH, 27)                        43   CH.sub.2 CO.sub.2 H                                                                    H   H  2    62  oil              +97.9  1720, 1650, 1400                                                        (1.0,  (CHCl.sub.3,                                                                   cm.sup.-1)                                                              MeOH, 27)                        44   CH.sub.2 CO.sub.2 H                                                                    2-OH                                                                               H  1    86  158-159                                                                             MeOHEtOAc   +144.8 3310, 1715, 1626,                                      (dec.)           (1.0,  1247, 1211, 934                                                         MeOH, 27)                        __________________________________________________________________________      *This crystal contains an equimolar ether as crystalline solvent.        

                                      TABLE VI                                     __________________________________________________________________________      ##STR34##                                                                                          Method                                                                         of                                                                             prepn.                     [α].sub.D deg.           Compd.               (Examp.                                                                             Yield     Recrystn.   (c, solv.,                                                                           IR                       No.  R.sup.14                                                                            R.sup.15                                                                             R  n No.) (%) mp. (°C.)                                                                     sovent      °C.)                                                                          (nujol,                  __________________________________________________________________________                                                           cm.sup.-1)               45   4-Me 2-OH  H  0 2    72   86-113           +124.0                                                                               3300, 1723, 1635,                                      (dec.)            (1.0, 1217, 1176, 913                                                          MeOH, 28)                      46   4-Me 2-OH  H  1 4    93  100-105           +128.8                                                                               3200, 1735, 1650,                                      (dec.)            (1.1, 1630, 1600,                                                              MeOH, 25)                                                                            1170, 910                47   4-Me 2-OAc H  1 4    57   93-96                                                                               benzene     +80.4 3560, 1768, 1721,                                                        (1.0, 1635, 1204, 1178,                                                        MeOH, 24)                                                                            918                      48   4-Me 2-OH, H  1 4    69  oil                     1730, 1650, 1610,                  4-OMe                                       1400, 1250, 1230,                                                              1100, 910                                                                      (CHCl.sub.3,                                                                   cm.sup.-1)               49   4-Me 2-OH, Me 1 2    80  106-107.5                                                                            EtOAc(i-Pr).sub.2 O                                                                              3360, 3160, 1720,                  4-OMe                                       1650, 1615, 1210,                                                              1180, 915                50   4-Me 2-OAc,                                                                               H  1 4    80  oil                     *                                  4-OMe                                                                51   4-Cl 2-OH  Me 1 2    86   65-79            +109.1                                                                               3200, 1726, 1660                                                         (1.0, 1625, 1205, 1092,                                                        MeOH, 27)                                                                            916                      52   4-Cl 2-NO.sub.2                                                                           Me 1 2    73  oil               -232.5                                                                               1730, 1659, 919                                                          (0.8, (CHCl.sub.3,                                                                   cm.sup.-1)                                                               MeOH, 27)                      53   4-OH 2-OH  H  1 2    88  133-134                                                                              EtOAcbenzene                                                                               +124.8                                                                               3460, 3330, 1720,                                      (dec.)            (1.0, 1652, 1580, 1207,                                                        MeOH, 25)                                                                            1166, 911, 847,                                                                768                      54   4-   2-OH  H  1 2    47  125.5-128.5                                                                          EtOHH.sub.2 O                                                                              +108.5                                                                               3480, 3412, 1710,             OCH.sub.2 Ph                               (1.0, 1624, 1605, 1572,                                                        MeOH, 25)                                                                            1261, 1246, 1220,                                                              1208, 1168, 920,                                                               838, 761, 742            55   4-OMe                                                                               4-Me  H  1 3    67  121-129                                                                              EtOAcether  +115.0                                                                               1720, 1637, 1620,                                                        (0.5, 1607, 926                                                                MeOH, 26)                      56   4-OMe                                                                               2-OH  H  1 3    80  160-161                                                                              MeOHEtOAcben-                                                                              +137.8                                                                               3260, 1736, 1653,                                      (dec.)                                                                               zene        (1.0, 1598, 1247, 1171,                                                        MeOH, 28)                                                                            916                      57   4-OMe                                                                               2-OMe H  1 1    76  166.5-167.5                                                                          EtOAcbenzene                                                                               +139.3                                                                               1734, 1637, 1603,                                                        (1.1, 913                                                                      MeOH, 27)                      58   3,4,5-                                                                              2-OH  H  1 4    69   97-101           +116.1                                                                               3200, 1730, 1650,             (OMe).sub.3                                (1.2, 1620, 1580, 1140,                                                        MeOH, 25)                                                                            1120, 820                59   3,4,5-                                                                              3,4,5-                                                                               Me 1 2    68   65-72            +111.0                                                                               1750, 1720, 1650,             (OMe).sub.3                                                                         (OMe).sub.3                           (1.2, 1630, 1590, 1320,                                                        MeOH, 27)                                                                            1125, 1000                                                                     (CHCl.sub.3,                                                                   cm.sup.-1)               60   4-OAc                                                                               2-OAc H  1 5    66   72-76            +67.6 1755, 1650, 1600,                                                        (0.7, 1190˜1200,                                                         MeOH, 24)                                                                            1160, 913                61   4-NHAc                                                                              2-OH  H  1 5    67   92.5-94          +100.6                                                                               3280, 1715, 1650,                                      (dec.)            (1.0, 1630, 1590, 1210,                                                        MeOH, 25)                                                                            1170, 912                62   4-NHAc                                                                              3,4-  Me 1 5    85   82-84            +112.4                                                                               3280, 1740, 1653,                  OCH.sub.2 O                           (1.0, 1625, 1593, 1520,                                                        MeOH, 25)                                                                            1460, 915                63   4-NHAc                                                                              4-NHAc                                                                               Me 1 5    55  oil               +144.6                                                                               3280, 1710, 1650,                                                        (0.9, 1635, 1599, 916                                                          MeOH, 26)                                                                            (neat,                   __________________________________________________________________________                                                           cm.sup.-1)                 *NMR (CDCl.sub.3, δ) 2.40 (3H, s), 2.43 (3H, s), 2.53- 3.50 (6H,        m), 3.73 (3H, s), 4.97 (1H, t, J = 6Hz), 6.20 (1H, s), 678. (1H, s),           7.00-7.48 (2H, m), 7.75, 8.03 (4H, A.sub.2 B.sub.2, each d, J = 8Hz), 8.4      (1H, br.s).                                                              

                                      TABLE VII                                    __________________________________________________________________________      ##STR35##                                                                                                    Meth-                                                                          od of                                                                          prepn.      Re-                                                                (Ex-        crystn.                                                                            [α].sub.D deg.            Compd.                         amp.                                                                               Yield                                                                              mp. sol-                                                                               (c, solv.,                                                                          IR                         No.  Q R.sup.9     R.sup.10                                                                           R.sup.5                                                                             R  No.)                                                                               (%) (°C.)                                                                       vent                                                                               °C.)                                                                         (nujol,                    __________________________________________________________________________                                                         cm.sup.-1)                 64   S CH.sub.2 OCOMe.sub.3                                                                       COPh                                                                               H    Me 6   91  69-69.5                                                                            ben-                                                                               -153.8                                                                              1770, 1751, 1655,                                                              1643,                                                                 zene-                                                                              (1.0,                                                                               1457, 1417, 1204,                                                              1102,                                                                 n-hex-                                                                             MeOH,                                                                               990, 912                                                              ane 25)                               65 S                                                                                 ##STR36##  COPh                                                                               H    Me 6   88  oil     -106.9 1.3, MeOH, 24)                                                               1757, 1740, 1662,                                                              1652, 1416, 1207,                                                              1070, 915 (neat,                                                               cm.sup.-)                    66 S                                                                                 ##STR37##  COPh                                                                               H    Me 6   90  62-64   -89.7 (0.7, MeOH, 25)                                                               1784, 1755, 1725,                                                              1650, 1456, 1408,                                                              1379, 1205, 915, 728         67 S                                                                                 ##STR38##  COPh                                                                               H    Me 6   92  99-100                                                                             ether                                                                              -131.6 (0.9, MeOH,                                                                  1772, 1739, 1707,                                                              1652, 1628, 1460,                                                              1170, 910, 729               68 S CH.sub.2 OCOCMe.sub.3                                                                      Ac                                                                                  ##STR39##                                                                          H  6   82  oil     +83.0 (0.7, MeOH, 25)                                                               1767, 1680, 1657,                                                              1404, 1172, 1111, 994                                                          CHCl.sub.3,                __________________________________________________________________________                                                         cm.sup.-1)            

                  TABLE VIII                                                       ______________________________________                                         Elementary Analysis                                                                                   Analysis (%)                                                                   Calcd.                                                                         (Found)                                                 Compd.                 .THorizBrace.                                           No.    Formula         C        H     N                                        ______________________________________                                          9     C.sub.15 H.sub.23 NO.sub.4 S.sub.2                                                             52.15    6.71  4.05                                                            (52.16)  (6.66)                                                                               (3.81)                                   11     C.sub.16 H.sub.19 NO.sub.4 S.sub.2                                                             54.37    5.42  3.96                                                            (54.28)  (5.38)                                                                               (3.95)                                   19     C.sub.15 H.sub.17 NO.sub.4 S.sub.2                                                             53.08    5.05  4.13                                                            (52.98)  (5.00)                                                                               (4.10)                                   20     C.sub.16 H.sub.19 NO.sub.4 S.sub.2                                                             54.37    5.42  3.96                                                            (54.24)  (5.36)                                                                               (4.02)                                   21     C.sub.16 H.sub.19 NO.sub.4 S.sub.2                                                             54.37    5.42  3.96                                                            (54.19)  (5.36)                                                                               (4.03)                                   22     C.sub.16 H.sub.19 NO.sub.4 S.sub.2                                                             54.37    5.42  3.96                                                            (54.55)  (3.38)                                                                               (3.94)                                   23     C.sub.18 H.sub.23 NO.sub.4 S.sub.2                                                             56.67    6.08  3.67                                                            (57.04)  (6.08)                                                                               (3.57)                                   24     C.sub.17 H.sub.21 NO.sub.4 S.sub.2                                                             55.56    5.76  3.81                                                            (55.77)  (5.73)                                                                               (3.58)                                   25     C.sub.17 H.sub.21 NO.sub.4 S.sub.2                                                             55.56    5.76  3.81                                                            (55.74)  (5.75)                                                                               (3.74)                                   26     C.sub.17 H.sub.19 NO.sub. 4 S.sub.2                                                            51.37    4.82  3.52                                                            (51.71)  (4.80)                                                                               (3.37)                                   27     C.sub.17 H.sub.20 N.sub.2 O.sub.3 S.sub.2                                                      51.50    5.08  7.07                                                            (51.32)  (5.06)                                                                               (7.02)                                   32     C.sub.17 H.sub.19 NO.sub.6 S.sub.2                                                             51.37    4.82  3.52                                                            (51.58)  (4.75)                                                                               (3.50)                                   35     C.sub.18 H.sub.23 NO.sub.4 S.sub.2                                                             56.67    6.08  3.67                                                            (56.10)  (5.83)                                                                               (3.43)                                   37     C.sub.19 H.sub.25 NO.sub.6 S.sub.2                                                             53.38    5.89  3.28                                                            (53.54)  (5.86)                                                                               (3.29)                                   40     C.sub.19 H.sub.18 N.sub.2 O.sub.5 S.sub.2.1/2H.sub.2 O                                         53.38    4.48  6.55                                                            (53.65)  (4.32)                                                                               (6.48)                                   41     C.sub.20 H.sub.19 ClN.sub.2 O.sub.5 S.sub.2                                                    51.44    4.10  6.00                                                            (51.10)  (4.05)                                                                               (5.88)                                   44     C.sub.15 H.sub.17 NO.sub.6 S.sub.2                                                             48.51    4.61  3.77                                                            (48.51)  (4.60)                                                                               (3.74)                                   46     C.sub.21 H.sub.22 NO.sub.5 S.sub.2                                                             58.45    4.90  3.25                                                            (58.58)  (5.01)                                                                               (3.21)                                   47     C.sub.23 H.sub.23 NO.sub.6 S.sub.2.1/2H.sub.2 O                                                57.25    5.01  2.90                                                            (57.51)  (5.07)                                                                               (2.62)                                   56     C.sub.21 H.sub.21 NO.sub.6 S.sub.2                                                             56.36    4.73  3.13                                                            (56.53)  (4.74)                                                                               (3.12)                                   58     C.sub.23 H.sub.25 NO.sub.8 S.sub.2                                                             54.42    4.96  2.76                                                            (54.17)  (4.99)                                                                               (2.73)                                   64     C.sub.21 H.sub.27 NO.sub.6 S.sub.2                                                             55.61    6.00  3.09                                                            (55.73)  (5.98)                                                                               (2.97)                                   66     C.sub.24 H.sub.22 N.sub.2 O.sub.6 S.sub.2.1/6C.sub.6 H.sub.6                                   58.69    4.53  5.48                                                            (58.66)  (4.41)                                                                               (5.82)                                   67     C.sub.25 H.sub.24 N.sub.2 O.sub.6 S.sub.2                                                      58.58    4.72  5.47                                                            (58.70)  (4.64)                                                                               (5.41)                                   ______________________________________                                    

Table IX shows the results of the pharmacological tests when the represented compounds of the compounds [I] of this invention and the related salts are used as antihypertensive agents. Table IX clearly shows that the compounds of this invention have the long-lasting, useful antihypertensive effect, and stability is also excellent.

PHARMACOLOGICAL TEST

As recently it has been clear that the compounds inhibiting angiotensin I-converting enzyme may be the curative potency against both renal hypertension and essential hypertension, the compounds of this invention are evaluated as antihypertensive agents by the following method.

(Method)

Male Wistar strain rats weighing 200-300 g were used. Under ether anesthesia, polyethylene cannulae are inserted into carotid artery and jugular vein. The cannula to carotid artery is connected to an electric transducer, while the cannula to jugular vein is connected to an apparatus for continuous infusion. After the complete recovery from anesthesia, angiotensin I is infused intravenously in a dose of 300 ng/kg by the apparatus for continuous infusion, and the pressor response is recorded by polygraph (Nihon Koden, RM-150). The compounds of this invention suspended in 0.5% tragacanth solution are addministered orally in a dose of 0.3 ml per 100 g of body weight, and the pressor response to angiotensin I infused intravenously is measured with time. The inhibitory activity of the compounds against angiotensin I-converting enzyme is expressed as the percent inhibition of pressor response to angiotensin I. Table IX shows the changes of percent inhibition of the compounds of this invention with time.

(Results)

The compounds of this invention as well as the known antihypertensive mercaptoacylamino acids suppress the pressor response to angiotensin I by administered orally to unanesthesized rats, the mechanism of which is derived from inhibiting angiotensin I-converting enzyme. The compounds of this invention are derivatives of mercaptoacylamino acid, and with the comparative result in the suppressive effect of pressor response to angiotensin I by administering these equimolar compounds orally it has been proved that the compounds of this invention are well absorbed from the gastroenteric wall, and hydrolyzed gradually at the part to be shown the activity so that they have the advantages as antihypertensive agent such as durability.

STABILITY TEST

The stability of mercaptoacylamino acids is compared with that of ester derivatives or S-acyl and S-alkyl derivatives in the ethanol or the phosphate buffer solution (pH 7.0).

Condition for preservation: at room temperature, for 1 month.

Result: Ester derivatives and S-acyl and S-alkyl derivatives are more stable than mercaptoacylamino acids.

TOXICITY TEST

The value of acute toxicity of (4R)-2-(2-acetoxyphenyl)-3-(S-acetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid (Compound 32) is LD>500 mg/kg.

(Experimental animals)

The male ddy-std. strain mice (4 weeks of age, weighing 19-21 g) were placed in a breeding room of constant temperature and humidity (23±1° C., 55±5%) and fed freely pellet diet (CE-2, Clea Japan, Inc.) and water ad. libitum for a week. The mice showing the normal growth were selected for the experiment.

(Method of administration)

Test compound is suspended in 0.5% tragacanth solution, and administered intraperitoneally in a dose of 0.5 ml per 20 g B.W.

                                      TABLE IX                                     __________________________________________________________________________     Compd.                                                                               Dose Inhibition (%)                                                      No.   (mg/kg)                                                                             5  15 25 35 45 55 65 75 85 95 105                                                                               115                                                                               (min.)                          __________________________________________________________________________      2    1.8  39.3                                                                              58.1                                                                              64.0                                                                              60.0                                                                              73.0                                                                              57.2                                                                              55.0                                                                              54.5                                                                              42.0                                                                              39.5                                                                              42.0                                                                              37.0                                2A   1.3  20.0                                                                              40.0                                                                              37.5                                                                              36.5                                                                              33.7                                                                              30.0                                                                              28.2                                                                              20.0                                                                              30.0                                                                              24.8                                                                              21.0                                                                              20.0                                2B   1.8   7.9                                                                              36.8                                                                              36.8                                                                              36.8                                                                              45.7                                                                              31.6                                                                              31.6                                                                              31.6                                                                              21.1                                                                              21.1                                                                              15.8                                                                              15.8                               22    1.5  45.2                                                                              60.4                                                                              51.4                                                                              59.0                                                                              55.0                                                                              50.8                                                                              55.0                                                                              53.5                                                                              49.4                                                                              46.5                                                                              39.8                                                                              31.6                               22A   1.0  34.0                                                                              51.5                                                                              49.7                                                                              45.0                                                                              37.5                                                                              30.2                                                                              30.2                                                                              30.2                                                                              28.0                                                                              19.8                                                                              10.2                                                                               8.0                               22B   1.4  45.4                                                                              60.7                                                                              60.6                                                                              45.4                                                                              45.4                                                                              45.4                                                                              42.4                                                                              36.4                                                                              30.3                                                                              21.2                                                                              21.2                                                                              21.2                               32    1.7  40.2                                                                              55.3                                                                              70.2                                                                              70.2                                                                              61.1                                                                              54.2                                                                              55.3                                                                              57.2                                                                              48.2                                                                              43.4                                                                              27.3                                  32C   1.3  53.3                                                                              62.9                                                                              64.7                                                                              63.7                                                                              54.0                                                                              49.3                                                                              47.7                                                                              38.8                                                                              34.0                                                                              30.0                                                                              30.0                                                                              31.0                               64    1.9  30.0                                                                              59.5                                                                              69.5                                                                              59.9                                                                              55.7                                                                              53.5                                                                              47.1                                                                              37.2                                                                              36.5                                                                              30.8                                                                              27.8                                                                              24.5                               __________________________________________________________________________      A. Corresponding thiol compounds.                                              B. Corresponding S--benzoyl compounds.                                         C. Corresponding thiol and phenolic hydroxy compound.                    

It is found from the above pharmacological tests that the compounds [I] to [V] of this invention are useful as antihypertensive agents having the lasting property. The compounds can be given with the combination of diuretics such as hydroflumethiazide, furosemide, and bumetanide same as other antihypertensive agents. The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. In the treatment of hypertension, these preparations can contain not only general excipients but also other antihypertensive agents such as reserpine, α-methyldopa, guanethidine, clonidine, hydralazine, etc. The dose is adjusted depending on symptom, dosage form, etc. But, usual daily dosage is 1 to 5000 mg, preferably 10 to 1000 mg, in one or a few divided doses.

EXAMPLES OF FORMULATION (1) Oral drug

    ______________________________________                                         (a)     tablet                                                                 ______________________________________                                         compound 2                30     mg                                            lactose                   150    mg                                            crystalline cellulose     50     mg                                            calcium carboxymethylcellulose                                                                           7      mg                                            magnesium stearate        3      mg                                            total                     240    mg                                            compound 22               30     mg                                            lactose                   150    mg                                            crystalline cellulose     50     mg                                            calcium carboxymethylcellulose                                                                           7      mg                                            magnesium stearate        3      mg                                            total                     240    mg                                            compound 9                150    mg                                            lactose                   60     mg                                            crystalline cellulose     30     mg                                            calcium carboxymethylcellulose                                                                           7      mg                                            magnesium stearate        3      mg                                            total                     250    mg                                            compound 32               150    mg                                            lactose                   60     mg                                            crystalline cellulose     30     mg                                            calcium carboxymethylcellulose                                                                           7      mg                                            magnesium stearate        3      mg                                            total                     250    mg                                            ______________________________________                                    

The tablets may be treated with common film-coating and further with sugar-coating.

    ______________________________________                                         (b)      granule                                                                        compound 53        30      mg                                                  polyvinylpyrrolidone                                                                              25      mg                                                  lactose            385     mg                                                  hydroxypropylcellulose                                                                            50      mg                                                  talc               10      mg                                                  total              500     mg                                                  compound 22        30      mg                                                  polyvinylpyrrolidone                                                                              25      mg                                                  lactose            385     mg                                                  hydroxypropylcellulose                                                                            50      mg                                                  talc               10      mg                                                  total              500     mg                                         (c)      powder                                                                         compound 64        30      mg                                                  lactose            500     mg                                                  starch             440     mg                                                  colloidal silica   30      mg                                                  total              1000    mg                                                  compound 22        30      mg                                                  lactose            500     mg                                                  starch             440     mg                                                  colloidal silica   30      mg                                                  total              1000    mg                                                  compound 9         300     mg                                                  lactose            230     mg                                                  starch             440     mg                                                  colloidal silica   30      mg                                                  total              1000    mg                                                  compound 32        300     mg                                                  lactose            230     mg                                                  starch             440     mg                                                  colloidal silica   30      mg                                                  total              1000    mg                                         (d)      capsule                                                                        compound 2         30      mg                                                  lactose            102     mg                                                  crystalline cellulose                                                                             56      mg                                                  colloidal silica   2       mg                                                  total              190     mg                                                  compound 22        30      mg                                                  lactose            102     mg                                                  crystalline cellulose                                                                             56      mg                                                  colloidal silica    2      mg                                                  total              190     mg                                                  compound 53        30      mg                                                  glycerol           349.98  mg                                                  butyl p-hydroxybenzoate                                                                           0.02    mg                                                  total              380     mg                                                  compound 64        30      mg                                                  glycerol           349.98  mg                                                  butyl p-hydroxybenzoate                                                                           0.02    mg                                                  total              380     mg                                         ______________________________________                                    

(2) Injection

1 to 30 mg of compound 2 is contained in 1 ml of the aqueous solution (pH 6.5-7.0). 

What we claim is:
 1. A compound of the formula (I) ##STR40## wherein Q is methylene;R^(a) is hydrogen, phenyl, alkoxy-lower alkyl, acyloxy-lower alkyl, imido-lower alkyl or substituted phenyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, acyl, acyloxy, halogen, nitro, amino, lower alkylamino, acylamino or carboxy; R^(b) is lower alkyl, aralkyl, lower alkanoyl, cycloalkanecarbonyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, halogen or lower alkoxy; R^(c) is hydroxyphenyl; andwherein the lower alkyl groups contain 1 to 6 carbon atoms, lower alkoxy groups contain 1 to 6 carbon atoms, aralkyl groups are phenyl-lower alkyl groups, acyloxy groups are lower alkanoyloxy, benzoyloxy, or benzyloxycarbonyloxy groups, acylamino groups are lower alkanoylamino, benzoylamino, or benzyloxycarbonylamino groups, and acyl group is acetyl or benzoyl groups; and Z is straight or branched alkylene with 1 to 3 carbon atoms; and salts thereof.
 2. A compound as in claim 1 wherein Z is --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ -- or --CH(CH₃)CH₂ --.
 3. A compound as in claim 1 wherein R^(b) is pivaloyl or 4-methylbenzoyl and R^(c) is 2-hydroxyphenyl.
 4. 5-(2-Hydroxyphenyl)-1-[(2S)-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid of the formula of claim
 1. 5. 5-(2-Hydroxyphenyl)-1-[S-(4-methylbenzoyl)-3-mercaptopropanoyl]-2-pyrrolidinecarboxylic acid of the formula of claim
 1. 6. A pharmaceutical composition comprising (i) a compound of the formula (I) ##STR41## wherein Q is methylene;R^(a) is hydrogen, phenyl, alkoxy-lower alkyl, acyloxy-lower alkyl, imido-lower alkyl or substituted phenyl wherein the substituent(s) is lower alkyl, lower alkoxy, hydroxy, acyl, acyloxy, halogen, nitro, amino, lower alkylamino, acylamino or carboxy; R^(b) is lower alkyl, aralkyl, lower alkanoyl, cycloalkanecarbonyl, phenyl-lower alkanoyl, pyridylcarbonyl, benzyloxycarbonyl, substituted benzoyl or substituted phenyl-lower alkanoyl wherein the substituent(s) is lower alkyl, halogen or lower alkoxy; R^(c) is phenyl, furyl, thienyl, pyridyl, naphthyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, acyloxy, mercapto, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino, lower alkylenedioxy or carboxy; andwherein the lower alkyl groups contain 1 to 6 carbon atoms, lower alkoxy groups contain 1 to 6 carbon atoms, aralkyl groups are phenyl-lower alkyl groups, acyloxy groups are lower alkanoyloxy, benzoyloxy, or benzyloxycarbonyloxy groups, acylamino groups are lower alkanoylamino, benzoylamino, or benzyloxycarbonylamino groups, acylmercapto groups are lower alkanoylmercapto, or benzoylmercapto groups, and acyl group is acetyl or benzoyl groups; and Z is straight or branched alkylene with 1 to 3 carbon atoms; and pharmaceutically acceptable salts thereof;in an amount sufficient to reduce blood pressure, and (ii) at least one pharmaceutically acceptable excipient.
 7. The composition of claim 6 wherein R^(c) is hydroxyphenyl.
 8. A method for reducing blood pressure in a warm blooded animal comprising administering the composition of claim 6 to said warm blooded animal.
 9. A method for reducing blood pressure in a warm blooded animal comprising administering the composition of claim 7 to said warm blooded animal. 